Am J Physiol. 1995 Jan;268(1 Pt 1):C259-70.  

Inhibition of cytochrome P-450 reduces voltage-gated K+ currents in pulmonary
arterial myocytes.

Yuan XJ, Tod ML, Rubin LJ, Blaustein MP.

Department of Medicine, Physiology, University of Maryland School of Medicine,
Baltimore 21201.

Cytochrome P-450 (P-450) is a NADPH-requiring and O2-dependent monooxygenase
system. It is present in lung and has been postulated to act as an O2 sensor in
hypoxic pulmonary vasoconstriction. To determine whether P-450 is involved in
the regulation of voltage-gated K+ (KV) channel activity in pulmonary artery
(PA) myocytes, we used the whole cell patch-clamp technique to evaluate the
effects of P-450 inhibitors on KV channel currents (IKV) and membrane potential
(Em). Bath application of the P-450 inhibitors clotrimazole, miconazole, and
1-aminobenzotriazole (1-ABT) significantly and reversibly inhibited steady-state
IKV (IKss) and depolarized PA cells bathed in either Ca(2+)-containing (1.8 mM)
or Ca(2+)-free [0.5-1 mM ethylene glycol-bis(beta-aminoethyl
ether)-N,N,N'N'-tetraacetic acid present] bath solution. Clotrimazole (1
microM), miconazole (10 microM), and 1-ABT (1 mM) reversibly reduced IKss,
elicited by a test potential of +80 mV, by 40, 70, and 31%, respectively.
Pretreatment of PA smooth muscle cells with 10 mM 4-aminopyridine (4-AP)
prevented the subsequent inhibitory effect of clotrimazole on IKV. However,
pretreatment of the cells with 1 mM tetraethylammonium negligibly altered the
effects of miconazole on IKV and Em. In current-clamp (I = 0) measurements,
clotrimazole depolarized PA myocytes by 9 and 11 mV during perfusion with
Ca(2+)-containing and Ca(2+)-free bath solution, respectively. 1-ABT also caused
a 9-mV depolarization in PA myocytes bathed in Ca(2+)-free solution. These
effects are similar to those induced by hypoxia, reduced glutathione, and 4-AP.
Clotrimazole also decreased IKV and depolarized mesenteric arterial myocytes.
These data raise the possibility that the P-450 system, due to its influence on
IKV and sensitivity to O2 tension and NADPH, may play a role in linking the
regulation of pulmonary vascular tone to the alteration of cellular redox status
through a common pathway of KV channel activity.

PMID: 7840155 [PubMed - indexed for MEDLINE]